The cornea and sclera make up the outer tunic of the eye. Each is a connective tissue containing collagen fibrils embedded in a proteoglycan-rich extrafibrillar matrix, wherein the cornea is uniquely transparent and the sclera is totally opaque. Both tissues require strength to maintain the excess pressure within the eye and to resist external knocks and forces applied by extraocular muscles during eye movement. The mechanical strength is provided by deposition of collagen in a lamellar structure, wherein the lamellae run parallel to the surface of the tissue. The sclera as the white part of the eye is a tough connective tissue and is continuous with the cornea. Scleral collagen is, in composition and arrangement, similar to that of normal skin, with wider fibrils and much more interwoven structure than in the cornea. The sclera has no optical role other than to provide support for the retina on the back of the eye, but it has important physiological functions as providing fluid outflow channels and mechanical functions in maintaining an eye shape. The limbus constitutes the border between the cornea and the sclera. Changes of the collagen structure of the sclera and conjunctiva are accompanied by a development of shortsightedness (myopia). The above-mentioned relationships are e.g. taught by K. M. Meek, Chapter 13, The Cornea and Sclera, pages 359 ff., of P. Frantzl (ed.) Collagen Structure and Mechanics, Springer 2008, ISBN: 978-0-387-73905-2.
Methods and apparatuses for a rejuvenation of human skin are known for example by names such as Needling method, a Laser therapy method, fractionated Laser ablation, or percutaneous collagen induction method. For the fractionated Laser ablation devices such as Fraxel®, for instance, are known and in use. A denaturation of collagen and, consequently, a “shrinking” of the tissue can also be achieved by radio frequency, for instance by a Thermage® device. Such methods and devices are generally based on an application of injuries in the skin by means of a mechanical or a thermal therapy device, wherein the injuries are followed by subsequent repair processes causing also a reconstitution of the collagen structure in the skin with its natural structure. A degradation of the destroyed tissue and the reconstitution of the collagen tissue rejuvenate the skin in its biomechanical and aesthetical properties. The current fractional Laser based methods with a focused Laser beam do preferably not destroy a surface of the skin, but as in meso-therapeutic methods or in percutaneous collagen induction therapy, also called “needling” as a perforation of the skin, there are certain disadvantages such as increased infection risk for the patient as well as for the therapist. With the Laser treatment methods a better control of the results can be achieved compared with the mechanical percutaneous methods and the current fractional Laser based methods. However, in both cases, micro bleedings in the stratum papillare of the skin are produced, either by means of a needle roller or by a light-induced perforation of end-arterioles in the skin. The micro bleedings cause a release of blood corpuscles and mainly thrombocytes from the perforated end-arterioles. From the thrombocytes, among others, growth factors, such as TGFβ3, VEGF, EGF, for example, are released. The growth factors promote the degradation and regeneration of degenerated dermal collagen as found in aged individuals or pathologically in scars. The so caused formation of directed collagen in the dermis results in a regeneration or rejuvenation of the skin to a certain degree. The above-mentioned treatment methods advantageously include a perioperative topical treatment with creams containing high doses of vitamins, as substantially vitamin C for achieving high local vitamin levels in the skin. Vitamin A and C are important cofactors or coenzymes for the formation of collagen and elastin in a target region of the skin for forming collagen and elastin.
Another coexisting method for skin rejuvenation and also for the sclera and conjunctiva is increasing a crosslinking between the single collagen fibers within the collagen structure of the skin, which gives the collagen tissue a rejuvenated and biomechanically much better elasticity and strength. Such an increase of the crosslinking between the single collagen fibers can be induced by a pretreatment of the skin with a Photosensitizer like Riboflavin containing and skin penetrating agent in combination with UVA light which activates a process similar to a lysyl oxidase process. Lysyl oxidase is an extracellular copper enzyme that catalyzes formation of aldehydes from lysine residues in collagen and elastin precursors. The aldehydes are highly reactive, and undergo spontaneous chemical reactions with other lysyl oxidase-derived aldehyde residues, or with unmodified lysine residues. This results in crosslinking of collagen and elastin, which is essential for stabilization of collagen fibrils and for the integrity and elasticity of mature elastin and, last but not least, for the skin. Complex crosslinks are formed in collagen and in elastin that differ in structure (source: Wikipedia). Crosslinking takes place in such a way that end parts of the collagen fibrils are connected with each other in a kind of a covalent connection, wherein the space between the collagen fibrils becomes shorter causing a contraction of the collagen tissue in that region. In other words, if the collagen tissue is contracted in the x/y direction and parallel to the skin surface the collagen tissue also grows in its thickness in an orthogonal z direction. An application of a photosensitizer agent containing e.g. Riboflavin in combination with an UVA light stimulates a process similar to the lysyl oxidase process and therefore the crosslinking.
EP 1 2177 266 A1 of the author of the present invention discloses a Laser therapy system for rejuvenation of the skin via a combined treatment of a first UVA light treatment for collagen crosslinking together with a second Laser light treatment with another light source for a subcutaneous Laser needling application. The integrated optical system allows a precise placement of the focus point or light spot, respectively, of the first UVA light and of the second Laser light treatment.
DE 10 2010 022 634 A1 discloses an ophthalmologic Laser therapy system comprising a pulsed Laser light source, a controllable optical system, a Hartman-Shack sensor and a control unit controlling a position of the laser light pulse and its energy, such that the Laser energy pulses can be controlled in space and energy so as to achieve determined and constant therapeutic results.
DE 10 2010 020 194 A1 discloses another ophthalmologic Laser therapy system substantially comprising another Laser light source, a controllable optical system, a detector unit and another control unit, wherein the system allows diagnosis of the cornea, laser cutting as well as a soft light treatment for stabilizing the cornea. For the stabilizing of the cornea or cuts within the cornea, respectively, the document teaches a treatment of said cuts with UVA light, such that collagen growing is induced and closes the cuts at least partly. However the UVA light is applied without taking a microstructure of the collagen into account, and it is believed that rather a crosslinking than a growth of new collagen takes place.
WO 2009 033 083 A1 gives a generic view of possible treatments and reactions of the sclera, conjunctiva and the cornea. Treatment of myopia and hyperopia by surgical techniques including corneal interventions, such as reshaping a surface curvature of the cornea, and of non-corneal manipulations, such as altering properties of the sclera, a ciliary muscle, zonules, or the lens, is described. Also a cutting of kerfs into portions of the sclera to improve the accommodation possibility is disclosed. However this increases the risk of infections. A generating of a low-level radiation is preferred for the treatment of the sclera and the ciliary muscle to improve a refraction of the eye, with a light energy not ablating tissue from the sclera or the ciliary muscle. In this document effects are described rather than a controlled collagen growth within the sclera, conjunctiva or cornea.
EP 2 108 347 A1 discloses another ophthalmologic Laser therapy system for a controlled cornea ablation, wherein a surface and thickness of the cornea is detected by an optical coherence tomography system (OCT) and a Laser light beam generated which is time-, energy- and space-controlled. Thus certain regions of the cornea with irregularities are detected via the OCR and controllably ablated by the Laser beam. The OCR imaging system has a resolution of some 10 μm in x/y direction and 3 μm in the z direction orthogonally to the surface of the cornea. The process of detecting, controlling and generating the Laser beam happens in real time. However the process takes only an ablation of cornea tissue into account but not a growing of new tissue. A shaping by the crosslinking of the collagen tissue is not mentioned, either.
WO 2007 082 127 A2 discloses a combination therapy for a long lasting controlled cerato-reformation (CRK), comprising a measurement of the total corneal topography, an ablation of parts of the cornea and an UVA light treatment for new collagen growth. For the UVA light induced collagen growth a photosensitizer is applied as Riboflavin (C3-R) in the form of eye drops which increases the amount of collagen crosslinking in the cornea. Thus the biomechanical rigidity of the cornea is taught to be increased. The light intensity is selected to be 3 mW/cm2, the wavelength is 365 nm and the time is 30 minutes.
US 2012 059 439 A1 discloses an aberration control by induced new collagen crosslinking combined with a beam shaping technique. It is taught that new collagen crosslinking is used to alter a characteristic of the cornea, such as thickness or refractive index to correct wavefront aberrations. The light intensity is 3 mW/cm2 and the wavelength is 365-370 nm. However, the UVA light is applied rather as a wide beam over an area of a certain part of the cornea and not as a focused light beam describing a pattern. Also, a tightening of the outer sclera to give the eyeball a corrected shape is not mentioned.
The induction of the crosslinking of the collagen by the UVA light must also be seen in connection with the fact that the UVA light has a cell toxic effect as well. So, the UVA energy or density, respectively, has to be reduced as much as possible, such that the desired rejuvenating effect is still achieved but with the least toxic effect possible. It seems that the mentioned methods and devices of the prior art do not sufficiently take into account the toxic effect of the UVA. According to the prior art the UVA light is applied with a relatively wide beam diameter in relation to the microstructure of the collagen with the collagen fibrils and the collagen fibril bundles.
Taking into account the microstructure of the collagen as a network of the collagen fibers and the process how the crosslinking is induced by the UVA light in combination with the photosensitizer, the UVA light should be applied as a focused light beam with the focus point describing a pattern within the microstructure of the collagen tissue so as to reduce the total UVA light energy per mm2 or mm3 for a certain crosslinking. Preferably the pattern of the focus point should be adaptable to an orientation of the collagen within a certain collagen layer. In other words, the UVA light energy should be focused on certain points or paths within a plane or within a spherical plane within the pattern, wherein the pattern comprises areas between the paths or points which are not irradiated with UVA light, such that the percentage of the non-irradiated areas could be seen as a reduction of total applied UVA energy. Furthermore, the crosslinking could preferably be controlled by a kind of a micro-treatment instead of a broad and general treatment according to the prior art. Such a micro-structural growth could also open up new possibilities of a refractive eye treatment.
The new collagen structure induced by the UVA light grows along existing collagen fibers of the collagen tissue. Also an orientation of the new collagen fibers is the same as that of the underlying existing collagen fibers. The UVA light induced growth of the new collagen structure requires a certain UVA energy density at the respective collagen fiber or more precisely on a surface of a collagen layer on which the new collagen structure grows.
Furthermore, the therapy of the whitening of the sclera and/or conjunctiva could be enhanced taking also a Laser needling therapy into account as it is known from treatments of normal skin. For the Laser Needling particularly the end-arterioles have to be made permeable for the corpuscular blood cells such that a further growth of additional new collagen is stimulated. This kind of stimulation can be achieved by a pulsed and focused Laser light beam with a focus point at the end-arteriole, by a Laser ablation or by a light energy strong enough to induce an optical breakdown. At least a capillary leak through protein denaturation of the vascular endothel shall be caused. The Laser Needling could also be used to weld varicose vessels in the sclera.
With regard to the rejuvenation of the sclera and/or conjunctiva under aesthetical aspects with the objective to whiten the eye the treatment could also take into account a combined treatment of the UVA light therapy and a kind of a Laser treatment for destroying varicose blood vessels. Advantageously the Laser therapeutic device should have both treatment possibilities integrated therein, such that a combined treatment could take place within a same treatment session.
Moreover, by inducing the crosslinking and the growth of the new collagen it is imaginable that said crosslinking and growth of the new collagen could be determined, such that the refractive system of the eye with an astigmatism could be corrected and Myopia and Hyperopia could be treated.
For clarity reasons the eye is to be understood as a living eye. The wording UVA light is equivalent to the wordings UVA energy or energy density, whatever is correct in the respective sense which is apparent to a person skilled in the art. The UVA light can also be a Laser light. The term collagen is equivalent with collagen tissue and collagen fibers or collagen fiber bundles, whatever is correct in the respective sense which is apparent for a person skilled in the art.